The long-term objective of this research is to determine how the viruses-associated human gut microbial community influence the stability of the healthy gut microbiome and help to resist change to a diseased state (dysbiosis). Preliminary results suggest that healthy humans host a relatively stable virome, which we define as the healthy gut virome (HGV). We postulate that like the healthy gut intestinal microbial community, that a healthy gut microbial virus community exists that contribute to the overall function and stability of the intestinal microbial community. This proposal will examine the role of viruses in influencing this homeostasis. We hypothesize that the HGV can be used therapeutically to both establish and maintain healthy microbiome function. This hypothesis will be tested by four specific aims; (i) defining the shared and unique components of the healthy gut virome (HGV), (ii) determining whether viruses govern the stability of the gut microbiome, (iii) determining whether HGVs accelerate microbiome recovery from antibiotic perturbation, (iv) and determining whether HGVs protect against dysbiosis- associated disease. The experimental approaches to accomplish the specific aims include analysis of a collection of human clinical samples, state-of-the-art genetic engineering, and the use of gnotobiotic mice models. The innovation of the proposed research includes the proposal that viruses play a direct, beneficial role in creating and maintaining the structuring of the healthy human gut microbiome and mouse model systems will be used to directly test the role of viruses associated with the gut microbiome in health and disease. This research leverages the research team's expertise in virology, the human gut microbiome, gnotobiotic mouse model systems and CRISPR genome editing technology to understand the role and use of the HGV in human health. The outcomes of this research will be to improve our fundamental understanding of viruses associated with the healthy gut microbiome and to ultimately impact clinical practice by providing new approaches for the beneficial use of viruses to advance human health.